EP2848617B1 - Diaryl[a,g-]chinolizidinverbindung, herstellungsverfahren dafür, pharmazeutische zusammensetzung und verwendungen davon - Google Patents

Diaryl[a,g-]chinolizidinverbindung, herstellungsverfahren dafür, pharmazeutische zusammensetzung und verwendungen davon Download PDF

Info

Publication number
EP2848617B1
EP2848617B1 EP13787305.5A EP13787305A EP2848617B1 EP 2848617 B1 EP2848617 B1 EP 2848617B1 EP 13787305 A EP13787305 A EP 13787305A EP 2848617 B1 EP2848617 B1 EP 2848617B1
Authority
EP
European Patent Office
Prior art keywords
methoxy
quinolizine
benzo
tetrahydro
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP13787305.5A
Other languages
English (en)
French (fr)
Other versions
EP2848617A4 (de
EP2848617A1 (de
Inventor
Hong Liu
Xuechu Zhen
Haifeng Sun
Liyuan ZHU
Wangke QIAN
Leiping YU
Zeng LI
Shengbin ZHOU
Wenxian CAI
Hualiang Jiang
Kaixian Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Publication of EP2848617A4 publication Critical patent/EP2848617A4/de
Publication of EP2848617A1 publication Critical patent/EP2848617A1/de
Application granted granted Critical
Publication of EP2848617B1 publication Critical patent/EP2848617B1/de
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to the field of pharmaceutical chemistry and chemotherapy. Specifically, the present invention relates to a class of diarylo[a,g]quinolizines according to claim 1 and derivatives thereof with a novel structure, a process for preparing the same, a pharmaceutical composition thereof; and a use thereof in preparing a medicament for treating a neurological disease, especially, Parkinson's disease, schizophrenia, mania, depression, drug addiction, migraine and the like, which involves in a dopamine receptor and a 5-HT receptor.
  • Neurological disease has been one of the prevalent diseases in contemporary society. However, many types of neurological disease have not yet been effectively addressed in clinical practice. Especially, the treatments for neurological diseases such as schizophrenia, Parkinson's disease and the like are still far from achieving a satisfactory result.
  • Schizophrenia is one of the most serious mental disorders, and has an incidence of up to 1% in a general population. Its clinical manifestation may be classified into positive symptoms represented by hallucination, delusion, exhilaration, playful behavior, etc., and negative symptoms represented by quiet, poverty of thought, abepithymia, abulia, degeneration of sociability etc. According to incomplete statistics, China has no less than 10 million of patients with schizophrenia. As the pace of life is quickened and the pressure of work is increased, schizophrenia tends to have an increasing incidence, and will cause heavy economic burden and social burden.
  • Clozapine Clozapine, Risperidone and so on, which share the similar characteristics of having an increased selectivity to D2 acceptor antagonistic action and a weaker side effect than the first-generation antipsychotic drugs.
  • These drugs can effectively improve the patients' positive symptoms including delusion, hallucination and so on, but still have weak activity on treating the negative symptoms of schizophrenia. Thus, there is a urgent need to design and develop new antipsychotic drugs.
  • the normal function of brain depends on appropriate amount of DA and its normal activity. It has been known that overactivity, especially the hyperfunction, of DA receptor, is related to the positive symptoms of schizophrenia, such as delusion, hallucination and the like, and abnormal activity of nigrostriatal DA is related to extrapyramidal symptoms.
  • the occurrence of the negative symptoms of schizophrenia and damage to cognitive function are related to DA activity, especially impairment of D1/NMDA receptors, in prefrontal cortex (mPFC), wherein hypofrontality of D1 in mPFC may be the key point.
  • mPFC prefrontal cortex
  • the currently known antipsychotic drugs are mainly based on antagonism against D2 receptor, and thus have poor therapeutic effect on negative symptoms.
  • such drugs cannot function to stabilize and recover normal DA activity in brain. Therefore, it is of great significance to develop new antipsychotic drugs having a dual function of D1 agonistic and D2 antagonistic activity and further balancing DA activities,
  • Parkinson's disease is a chronic progressive degenerative disorder, which is mainly characterized by the dopaminergic neuron loss in the substantia nigra.
  • L-Dopamine is a "gold standard” for the treatment of Parkinson's disease.
  • long-term administration of L-Dopamine is often accompanied by high incidence of treatment-related complication, such as dyskinesias, efficacy loss and "on-off” phenomenon and the like, which are named as "L-Dopamine long-term syndrom", and the disease progression can not be delayed.
  • DA receptor agonist is one of various substitutive therapies for Parkinson's disease and mainly used with L-Dopamine in Parkinson's having dyskinesia.
  • DA receptor agonist is superior to L-Dopamine for the following mechanism.
  • dopamine decarboxylase activity of the nigrostriatal dopaminerigic system is depleted, exogenous L-Dopamine can not be transformed into DA through decarboxylation, and at this time, even a large dose of L-Dopamine preparation is ineffective.
  • the function of DA receptor agonist is irrelevant to DA synthesis and does not depend on the activity of dopadecarboxylase.
  • DA receptor agonist can further improve the motor symptoms of Parkinson's disease.
  • a D1 receptor agonist with selectivity it will be possible to provide a class of drugs with good effect for the treatment of Parkinson's disease. So far, many D1 receptor agonists with selectivity have been developed in various large companies, and many of them are in clinical trails. However, many drug candidates have low selectivity and obvious side effects. Therefore, it will undoubtedly have huge advantages and provide wide space for the treatment of Parkinson's disease to develope a D1 receptor selective agonist with high selectivity and little side effect.
  • Diarylo[a,g]quinolizines have a common chemical core structure, andvarious biological activities, including anti-inflammatory effect, antibacterial effect, anti-leukemia effect, anti-cancer effect and so on.
  • Jin Guozhang an academician of Chinese Academy of Sciences, together with others systematically studied the pharmacological activities of 6 H -dibenzo[a,g]quinolizines and confirned that levorotatory tetrahydropalmatine has good analgesic effect with sedation, tranquillizing and hypnotic effects, while dextrorotatory tetrahydropalmatine has no significant analgesic effect.
  • levorotatory Chloroscoulerine and 1-SPD derivatives with antipsychotic effect, and pareparation methods and uses thereof, and especially levorotatory Scoulerine methanesulfonate with good water solubility and stability ( WO2008/014661 , CN03151464 , and CN1900076 ).
  • these compounds have a structure which has little room to be modified, and most of them have weak activity on D2 receptor, and many of them have no 5-HT activity with poor solubility and low bioavailability. Meanwhile, these compounds showed a certain degree of selectivity in D1 receptor vs D2 receptor. Therefore, it is of significance to continually modify diarylo[a,g]quinolizines, especially to develop a compound with better D2 activity or a D1 receptor agonist with better selectivity, thereby providing beneficial help for the treatment of Parkinson's disease.
  • WO 2010/075469 A1 refers to lipid lowering compounds and methods of making and using such compounds.
  • JP S50 24299 A relates to a method for making a heterocyclic compound.
  • WO 2008/014661 A1 relates to the field of medicinal chemistry and chemotherapeutics, in particular to the synthesis of a class of tetrahydroprotoberberines and their use in the preparation of drugs for the treatment of nervous system diseases, especially in the field of dopamine receptor neurological diseases.
  • EP 0 524 004 A1 relates to various decahydro-8H-isoquino [2,1-g][1,6]naphthyridine and decahydro-benzo[ a ]pyrrolo[2,3-e]quinolizine derivatives, as single enantiomers or racemic or non-racemic mixtures thereof, which exhibit selective ⁇ 2 -adrenoceptor blockade in mammals, and which, therefore, are useful as medicaments for the treatment of physiological conditions affected by such blockade.
  • WO 2007/006212 A1 relates to tetrahydroprotoberberine compounds, the synthetic method and the use thereof.
  • the compounds possess valuable therapeutic properties and are suitable, especially, for treating diseases that respond to modulation of dopamine receptors, such as schizophrenia, parkinsonism, hyperactivity disorder or migraine et.al.
  • WO 94/22858 A1 relates to tetracyclic compounds, which are selective dopamine agonists useful for treating dopamine-related neurological, psychological, cardiovascular, cognitive and behavioral disorders.
  • WO 97/36902 relates to novel trans-2,6-, 3,6- and 4,6-diaza-5,6,6a,7,8,12b-hexahydro-benzo[c]phenanthrene compounds which are selective dopamine agonists useful for treating dopamine-related neurological, psychological, cardiovascular, cognitive and behavioral disorders
  • the present invention provides a class of diarylo[a,g]quinolines with novel structures, and the synthesis and use thereof. Some of the compounds with such structure show good selectiviy for D1 vs D2, and many of the compounds also have 5-HT activity. In addition, some of the compounds have dual pharmacological activities of good D1 agonist and D2 antagonist with good solubility, and can be used in the preparation of a medicament for treating neurological disease, especially those associated with dopamine receptors and serotonin receptor.
  • One object of the invention is to provide a class of diarylo[a,g]quinolizidines according to claim 1, enantiomers, diastereoisomers, and racemates thereof, as well as pharmaceutically acceptable salts, and solvates thereof.
  • Another object of the invention is to provide a process for preparing the diarylo[a,g]quinolizidines according to claim 1.
  • Still another object of the invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising one or more selected from the group consisting of the diarylo[a,g]quinolizines according to claim 1, enantiomers, diastereoisomers, and racemates thereof, as well as pharmaceutically acceptable salts, and solvates thereof.
  • Still another object of the invention is to provide a use of the above-said compounds of claim 1 in preparing a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors, specially, a medicament for treating or preventing a disease such as schizophrenia, Parkinson's disease, mania, depression, drug addiction, migraine and the like.
  • the present invention relates to a diarylo[a,g]quinolizidine compound of of claim 1, an enantiomer, diastereoisomer, a racemate thereof, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate thereof.
  • the diarylo[a,g]quinolizine compound according to claim 1 is selected from the group consisting of No. Name Structure AS001 (S)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydr o-5 H -benzo[g]thieno[3,2-a]quinolizine AS002 (R)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydr o-5 H -benzo[g]thieno[3,2-a]quinolizine AS003 (S)-2-methyl-8-methoxy-9-hydroxy-4,7, 12, 12a-tetrahydro-5 H -benzo[g]thieno [3,2-a]quinolizin e AS004 (R)-2-methyl-8-methoxy-9-hydroxy-4,7,12,12a -tetrahydro-5 H -benzo[g]thieno[3,2-a]quinolizin e AS005 (S)-2-ethyl-8-methoxy-9-hydroxy-4,
  • diarylo[a,g]quinolizine compounds referred to as reference examples as also indicated further below: No. Name Structure AS011 (S)-2-cyclopropylmethyl-8-methoxy-9-hydroxy -4,7,12,12a-tetrahydro-5 H -benzo[g] thieno [3,2-a]quinolizine AS012 (S)-2-cyclobutylmethyl-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5 H -benzo[g]thieno[3,2-a]quinolizine AS020 (S)-2-(3-bromopropyl)-8-methoxy-9-hydroxy-4,7,12,12a-tetrahydro-5 H -benzo[g]thieno[3,2-a]quinolizine AS021 (S)-2-(2,2,2-trifluoroethyl)-8-methoxy-9-hydro xy-4,7,12,12a-tetrahydro-5
  • the "pharmaceutically acceptable salt” is a conventional non-toxic salt formed by reacting the compounds of claim 1 with an inorganic or organic acid.
  • a conventional non-toxic salt may be a salt prepared by reacting the compounds of claim 1 with an inorganic acid including HCl, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, and the like, or an organic acid including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalene sulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid
  • the present invention also provides a process for preparing the compounds of claim 1. Unless otherwise stated, the raw materials and reagents used in the present invention are commercially available.
  • Another object of the present invention is to provide a process for preparing the diarylo[a,g]quinolizine compounds of claim 1, enantiomers, diastereoisomers and racemates thereof, pharmaceutically acceptable salts thereof, crystalline hydrates or solvates thereof, which is carried out as one of the following menthods:
  • Method A the method A comprises :
  • Method B the method B comprises:
  • a1, a2 and b2 as starting materials are commercially available or may be prepared by conventional reactions.
  • AS001-AS030AS038-AS053, AF001-AF019, AI002-AI007 and AP001-AP006 may be prepared according to the method A, wherein, in the method A for AS001-AS030, AS038-AS044, AS047-AS053, AF001-AF006, AI002-AI007 and AP004-AP006, a1 and a2 as starting materials may be purchased commercially or prepared according to the conventional methods in the art, for example, the following Route A-1.
  • a1 as a starting material may be commercially available or prepared according to conventional methods in the art, for example, the following Route A-2; and in the method A, a2 as a starting material may be prepared accoriding to the same route as Route A-1.
  • Step h 8a is prepared through a substitution reaction of 7a in the presence of a copper catalyst under an alkaline condition, optionally under microwave;
  • the copper catalyst may be one or two selected from the group consisting of copper sulphate, copper oxide, copper powder, copper chloride, copper bromide, copper iodide, copper carbonate, copper nitrate, copper hydroxide and the like, preferably one or two selected from the group consisting of ocopper sulfate, copper oxide, and copper powder;
  • the reaction is carried out under an alkaline condition in the presence of a base such as NaOH, KOH, CeOH, Ca(OH)2, Ba(OH)2 or a quaternary ammonium base, preferably NaOH, KOH or CeOH;
  • the reaction is optionally carried out under the assistance of microwave, the reaction temperature is in a range of 90°C -150°C.
  • the method is a very effective method for producing a phenolic hydroxy group.
  • 8a having a relative high purity may be obtained by adjusting the pH value of the reaction mixture to 1-3 after the reaction. If further purification is necessary, one or two solvents selected from the group consisting of ethyl acetate, n-hexane, benzene, toluene, petroleum ether, ethanol, isopropanol, methanol, chloroform and xylene, preferably, toluene, xylene, and benzene may be used to perform a recrystallization.
  • Step i 9a is prepared through a cyclization of 8a in the presence of formaldehyde, which may be perfomed by referring to Richard J. Spangler, Brian G. Beckmann, Jong Ho Kim, J. Org Chem, 1977, 42, 2989-2996 , And Mark Cushman, Frederick W. Dekow, J.
  • 8a is refluxed in toluene with 2.0 to 3.0 equivalents of phenylboronic acid for 1 hour, added with paraformaldehyde and toluene, and kept at 100 °C for 46 hours.
  • the reaction mixuture is evaporated to dryness, reacted in water solution for 2 hours, and extracted with dichloromethane.
  • the organic phase is dried over sodium sulfate, evaporated to dryness, stirred for three hours in diethyl ether and filtered to give 9a.
  • Step j 10a is prepared by a substitution of 9a with an alkylating agent or a benzylating reagent; specifically, 9a is reacted with an alkylating agent (e.g., dimethyl sulfate, methyl iodide, diazomethane, methyl trifluoromethylsulfonate, or other alkylating agents), an acylating agent (e.g., acetyl chloride, acetic anhydride, benzoyl chloride, trifluoroacetic anhydride, etc.), or a benzylating reagent (e.g., substituted benzyl chloride, benzyl bromide and other benzylating reagents), preferably benzyl chloride, benzyl bromide, methyl iodide, dimethyl sulfate, acetyl chloride, or acetic anhydride, in the presence of an organic or inorganic base to give 10a.
  • the solvent used is one or more selected from the group consisting of methanol, ethanol, acetone, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform and dioxane, preferably acetone, tetrahydrofuran or N,N-dimethylformamide.
  • the inorganic base is one or more selected from the group consisting of NaOH, KOH, CeOH, Ba(OH)2, KH, NaH, sodium tert-butoxide, potassium tert-butoxide, K2CO3, Na 2 CO 3 and CaCO 3
  • the organic base is one or more selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline and N,N-dimethylpyridine, and preferably K 2 CO 3 is used.
  • Step 1 1b is prepared by a F-C acylation reaction of b with R 4 COCl in the presenc of a Lewis acid;
  • 1b is dissolved in an appropriate amount of glacial acetic acid, and added with 1.2 to 2.0 equivalents of ammonium acetate, and then with 5-10 equivalents of nitromethane at room temperature.
  • the reaction mixture is moved in an oil bath at 80 °C for 10 hours, cooled at room temperature to precipitate a large amount of solid, which is filtered to give 2b;
  • X is O, S or N;
  • R4 is hydrogen, unsubstituted or halogen-substituted C1-C5 straight or branched alkyl, or unsubstituted or substituted benzyl .
  • R9' is hydrogen, C1-C6 straight or branched alkyl
  • R5' is unsubstituted or halogen-substituted C1-C6 straight or branched alkyl, unsubstituted or substituted benzyl
  • R6 ' is unsubstituted or halogen-substituted C1-C6 straight or branched alkyl, unsubstituted or substituted benzyl , wherein the substituent for the substitution is C1-C6 straight or branched alkyl, halogen or C1- C6 straight or branched alkyloxy;
  • the aromatic ring suitable for the routes A-1 and A-2 may preferably be a benzene ring, thiophene, furan, indole, pyrrole, pyridine, or the like.
  • a 5-membered heterocycle is exemplified.
  • AS031-AS037, AI001, AI008-AI010, SBE01 and FBS01 may be prepared according to the method B.
  • DS001-DS052, DF001-DF009, DP001-DP006, SS001-SS002, SF001, FS001 and IS001-IS004 may be prepared according to Method B.
  • the starting material b2 for DS001-DS040, DS045-DS052, DF001-DF006, DP001-DP002, DP004-DP005, SS001-SS002, SF001, FS001, PP001-PP004 and IS001-IS004 can be purchased commercially or prepared by a conventional method, such as the following Route B-1.
  • Route B-1 Step a: the step is the same as step a in Route A-1;
  • Step 1 the step is the same as step a in Route A-1;
  • the present inventor found through experiments that the compounds of claim 1 have excellent selectivity for D1 receptor and 5-HT receptor activity.
  • the compound according to the present invention can be used in preparing an experimental model drug related to dopamine receptors and 5-HT receptors or in preparing a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.
  • the disease related to dopamine receptors and 5-HT receptors may be a neurological disease such as schizophrenia, Parkinson's disease, mania, depression, drug addiction, migraine or the like.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the compounds of claim 1, enantiomers, diastereoisomers and racemates thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further contain one or more conventional additives such as an odor agent, a flavoring agent and the like.
  • the pharmaceutical composition of the present invention preferably contains 1-99%, more preferably 65%-99% by weight of the compounds of claim 1 as an active ingredient, based on the total weight of the pharmaceutical composition, and the remaining amount of the pharmaceutically acceptable carriers and/ or conventional additives.
  • the compound and the pharmaceutical composition of the invention may be provided in various preparations such as tablet, capsule, powder, syrup, solution, suspension, aerosol and the like, and may be present in a suitable solid or liquid carrier or diluent, or a suitable disinfection appliance for injection or infusion.
  • the pharmaceutical composition of the invention may be prepared in various dosage forms according to conventional preparation methods in the pharmaceutical art. It may contain 0.05-200mg, preferably, 0.1mg-100mg of the compounds of claim 1 per unit dosage in the formulation of the preparation.
  • the compound and pharmaceutical composition of the present invention may be cinically used in mammals, including humans and animals, and can be administered orally, nosally, transdermally, pulmonarily, or gastrointestinally. Oral administration is the most preferred.
  • the most preferred daily dose is 0.01-200 mg/kg body weight and administered once daily, or 0.01-100 mg/kg body weight and administered several times a day. No matter what kind of administrating method is used, the optimal dose regimen for an individual should be based on the specific treatment Protocol. Generally, starting from a small dose, the dose is gradually increased until an optimal dose is achieved.
  • Methyl 3-bromo-4-benzyloxyphenylacetate (1.5g), KOH (1.5g), copper powder (0.15g), and CuO powder (0.15g) were dispersed in 8mL of water, agitated at room temperature for 10min, and degassed ultrasonically. The reaction was performed at 140 °C under microwave for 45min. After the reaction was completed, Cu and CuO were removed by filtration, and pH was adjusted with concentrated HCl to be acidic to precipitate a white solid, which was filtered to give crude 3-hydroxy-4-benzyloxyphenylacetic acid. The solid was dissolved in methanol, added with an appropriate amount of active carbon, refluxed for 30 minutes and decolored. Purification by column chromatography gave a white solid. Yield, 56%.
  • 3-hydroxy-4-benzyloxyphenylacetic acid (3.0g) and phenylboronic acid (3.0g) were dissolved in redistilled toluene (60mL), and refluxed at 110 °C for 1 hour.
  • the produced water was removed by an oil-water separation device.
  • Paraformaldehyde (3g) and an appropriate amount of molecular sieve (4 ⁇ ) were added into a pressure bottle, and the hot reaction mixture was poured into the pressure bottle. The reaction was performed at 100 °C for 46 hours. After the reaction was completed, the hot reaction mixture was filtered to remove the molecular sieve, and filtrate was evaporated to dryness to obtain a yellowish solid.
  • N-(thiopheneethyl)-2-hydroxy-3-methoxy-4-benzyloxyphenylacetamide was dissolved in a small amount of anhydrous dichloromethane, added with pyridine (3eq) and a catalytic amount of DMAP, followed by dropwise addition of acetyl chloride in ice bath. After the addition, the ice bath was removed and the reaction was preformed at room temperature. After the reaction was completed, the reaction mixture was washed with 1 N HCl, and extracted. The organic phase was dried, evaporated to dryness. And the resisue was purified by column chromatography to give a white solid. Yield, 92%.
  • N-(thiopheneethyl)-2-acetoxy-3-methoxy-4-benzyloxyphenylacetamide (1.19g) was dissolved in an appropriate amount of anhydrous acetonitrile and refluxed, followed by addition of POCl 3 (3 eq).
  • the reaction was preformed under nitrogen for 0.5 hour and monitored by TLC.
  • the reaction mixture was evaporated to dryness, and the residue was dissovled in a small amount of dichloromethane, added with saturated NaHCO 3 aqueous solution to be adjusted to be alkaline, and extracted triply with dichloromethane.
  • the organic phase was washed with saturated brine, dried over sodium sulphate, and evaporated to dryness to give yellow oily crude without further purification.
  • the product (1.07g) of last step was dissolved in a small amount of DMF (5ml), added with a catalyst (R,R)-Noyori(0.02 eq), and then with a mixture of formic acid/triethanolamine (0.5ml/0.2ml/1mmol raw material).
  • the reaction was preformed at room temperature for about 8 hours.
  • the reaction mixture was added with saturated NaHCO 3 aqueous solution to be adjusted to be alkaline, added with a large amount of water, and extracted triply with ethyl acetate.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulphate and evaporated to dryness to give a dark green solid.
  • (S,S)-Noyori was used to catalyze the reaction, a product in R-configuration was obtained.
  • the product (1.21g) of last step was dissolved in a mixture of ethanol (6 mL) and water (2 mL) and stirred at room temperature, followed by addition of NaOH(170 mg, 2 eq). The reaction was preformed for about 2 hours. After that, the reaction mixture was evaporated to remove part of the solvent, and extracted triply with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulphate and evaporated to dryness to give a light green solid.
  • the reaction mixture of last step was added with saturated NaHCO 3 solution to adjust its pH to be alkaline, and stirred at room temperature for 2 hours.
  • the reaction was monitored by TLC.
  • the reaction mixture was extracted triply with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by column chromatography to give the target product.
  • the titled product was prepared by the same procedure as that in example 1, except that (S,S)-Noyori catalyst was used to replace (R,R)-Noyori.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.
  • the titled product was prepared by the same procedure as that in example 2, except that 5-methylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-ethylthiophene-2-aldehyde was used to replace thiophene-2-aldehyde.
  • 2-propionylthiophene (1.5g) was dissolved in trifluoroacetic acid (10 mL) at 0 °C, added with 4 eq of triethyl silane, and stirred at room temperature overnight. Purification by column chromatography gave 2-n-propylthiophene. Yield, 92 % .
  • 2-n-propylthiophene was dissolved in anhydrous dichloromethane at 0 °C, and slowly added with titanium tetrachloride and dichloromethylether. The reaction was preformed at 0 °C to room temperature for about 1 hour. TLC showed that the reaction was completed. The reaction mixture was treated with ice water under agitating, and extracted with dichloromethane. The organic phase was evaporated to dryness to give 5-n-propyl thiophene-2-aldehyde.
  • the titled product was prepared by the same procedure as that in example 6, except that n-butyrylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that valerylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2-methylpropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 3-methylbutyrylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2-cyclopropylformylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2-cyclobutylformylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2,2-dimethylpropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2,2-dimethylbutyrylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2-methylbutyrylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2-chloroacetylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 3-chloropropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2-chloropropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 4-chlorobutyrylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 3-bromopropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 6, except that 2,2,2-trifluoroacetylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 1, except that 7,8-dimethoxy-3-isochromanone was used to replace thiophene-2-aldehyde.
  • the titled product was prepared by the same procedure as that in example 22, except that 5-methyl-thiophene-2-aldehyde was used to replace thiophene-2-aldehyde.
  • the titled product was prepared by the same procedure as that in example 22, except that 5-ethyl-2-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 22, except that 5-n-propyl-2-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 22, except that 2-methylpropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 22, except that 2-cyclopropylformylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 22, except that 2,2-dimethylpropionylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 22, except that 2-chloroacetylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 22, except that 2,2,2-trifluoroacetylchloride was used to replace propionylchloride.
  • the titled product was prepared by the same procedure as that in example 31, except that 5-methylthiophene-2-ethylamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 31, except that 5-ethylthiophene-2-ethylamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 31, except that 5-(2-methylpropyl)thiophene-2-ethylamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 31, except that 5-cyclopropylmethylthiophene-2-ethylamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 31, except that 5-(2-chloroethyl)thiophene-2-ethylamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 31, except that 5-(2,2,2-trifluoroethyl)thiophene-2-ethylamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methylthiophene-2-ethylketone was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methyl-2-thienal and nitroethane were used to replace 2-thienal and nitromethane.
  • the titled product was prepared by the same procedure as that in example 1, except that metaldehyde was used to replace paraformaldehyde.
  • the titled product was prepared by the same procedure as that in example 1, except that chloroformylchloride was used to replace paraformaldehyde.
  • the titled product was prepared by the same procedure as that in example 1, except that 4,5-dimethyl-2-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-2-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-fluoro-2-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methyl-3-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-3-thienal was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 7-acetoxy-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 1, except that 7-(2'-hydroxyethoxy)-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 1, except that 7-(2'-dimethylaminoethoxy)-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 1, except that 7-acetamido-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 1, except that 7-acetamido-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 1, except that 7-methylsulfonylamido-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 1, except that 2-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methyl-2-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-ethyl-2-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 6, except that 5-(2-methylpropyl)-2-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-cyclopropylmethyl-2-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-(2-chloroethyl)-2-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 45, except that 5-methyl-3-furfural was used.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-ethyl-3-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-(2-chloroethyl)-3-furfural was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 31, except that tryptamine was used to replace thiophene-2-ethylamine and 3,4-dimethoxyphenylacetic acid was used to replace 2,5-dimethoxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 1, except that tryptamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxytryptamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methyltryptamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-fluorotryptamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 1, except that 6-methyltryptamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 1, except that 6-methoxytryptamine was used to replace thiophene-2-ethylamine.
  • the titled product was prepared by the same procedure as that in example 62, except that 3,4-methylenedioxyphenylacetic acid was used to replace 3,4-dimethoxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 69, except that 3-methoxy 4-hydroxy phenylacetic acid was used to replace 3,4-methenedioxy phenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 69, except that 3-hydroxy 4-methoxy phenylacetic acid was used to replace 3,4-methenedioxy phenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-3-pyrrolecarboxaldehyde was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-3-pyridinecarboxaldehyde was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-6-hydroxy-3-pyridinecarboxaldehyde was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-methoxy-2-pyrrolecarboxaldehyde was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 6-methoxy-2-pyridinecarboxaldehyde was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in example 1, except that 5-hydroxy-6-methoxy-2-pyridinecarboxaldehyde was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in step 1.1 of example 1, except that the product obtained from the last step was used to replace 2-thienal.
  • the titled product was prepared by the same procedure as that in step 1.2 of example 1, except that the product obtained from the last step was used to replace 2-(2-nitrovinyl)thiophene.
  • the titled product was prepared by the same procedure as that in step 31.1 of example 31, except that the product obtained from the last step was used to replace thiophene-2-ethylamine and 3-methoxy-4-benzyloxyphenylacetic acid was used to replace 2,5-dimethoxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in step 1.10 of example 1, except that the product obtained from the last step was used to replace N-thienylethyl-2-acetyloxy-3-methoxy-4-benzyloxyphenylacetamide.
  • the titled product was prepared by the same procedure as that in step 1.11 of example 1, except that the product obtained from the last step was used to replace 2-methoxy-3-benzyloxy-6-((6,7-dihydro-thieno(3,2-c)pyridin-4-yl)-methyl)-benzyl acetate.
  • the titled product was prepared by the same procedure as that in step 31.2 of example 31, except that the product obtained from the last step was used to replace (S)-4-(2,5-dimethoxy benzyl)- 4,5,6,7-tetrahydro-thieno(3,2-c)pyridine.
  • the titled product was prepared by the same procedure as that in step 1.14 of example 1, except that the product obtained from the last step was used to replace (S)-4-(2-chloromethyl-3-methoxy-4-benzyloxy)-4,5,6,7-tetrahydro-thieno(3,2-c)pyridine).
  • the titled product was prepared by the same procedure as that in example 78, except that (S,S)-Noyori catalyst was used to replace (R,R)-Noyori catalyst.
  • the titled product was prepared by the same procedure as that in step 78.1 of example 78, except that the product obtained from the last step was used to replace ethyl thiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 78, except that the product obtained from the last step was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that (S,S)-Noyori catalyst was used to replace (R,R)-Noyori catalyst.
  • the titled product was prepared by the same procedure as that in example 80, except that propionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 2-methylpropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that n-butyryl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 3-methylbutyryl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that valeryl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 4-methylvaleryl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that cyclopropylformyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that cyclobutylformyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 2-chloroacetyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 2-chloropropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 3-chloropropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 4-chlorobutyryl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 2,2,2-trifluoroacetyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 3,3,3-trifluoropropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that 3,3-difluoropropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 78, except that 3,4-dimethoxyphenylacetic acid was used to replace 3-methoxy-4-benzyloxy-phenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 3,4-dimethoxyphenylacetic acid was used to replace 3-methoxy-4-benzyloxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 98, except that 2-methylpropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 98, except that 2-chloroacetyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 78, except that 3,4-methylenedioxyphenylacetic acid was used to replace 3-methoxy-4-benzyloxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 98, except that 3,4-methylenedioxyphenylacetic acid was used to replace 3,4-dimethoxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 102, except that 2-methylpropionyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 102, except that 2-chloroacetyl chloride was used to replace acetyl chloride.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-chloromethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-fluoromethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methylolthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methoxymethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-methoxythiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 4,5-dimethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 4-methylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 4-ethylthiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 103, except that acetaldehyde was used to replace formaldehyde.
  • the titled product was prepared by the same procedure as that in example 83, except that 2-methyl-2-(3-methoxy-4-hydroxyphenyl)ethylamine was used to replace 3-methoxy-4-hydroxyphenylethylamine.
  • the titled product was prepared by the same procedure as that in example 83, except that 1-methyl-2-(3-methoxy-4-hydroxyphenyl)ethylamine was used to replace 3-methoxy-4-hydroxyphenylethylamine.
  • the titled product was prepared by the same procedure as that in example 83, except that 2-fluoro-2-(3-methoxy-4-hydroxyphenyl)ethylamine was used to replace 3-methoxy-4-hydroxyphenylethylamine.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-ethylthiophene-3-acetic acid was used to replace 5-ethylthiophene-3-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(2-chloroethyl)thiophene-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(2-methyl propyl)thiophene-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-methoxythiophene-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that furan-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-ethylfuran-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(2-methylpropyl)furan-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-cyclopropylmethylfuran-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(2-chloroethyl)furan-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-methoxyfuran-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-ethylfuran-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(2-methylpropyl)furan-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(2-chloroethyl)furan-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that pyrrole-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-methoxypyrrole-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-methoxypyrrole-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that pyridine-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 4-methoxy-5-hydroxypyridine-2-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 6-methoxypyridine-3-acetic acid was used to replace 5-ethylthiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that 5-methyl-2-thienal was used to replace 3-methoxy-4-benzyloxybenzaldehyde and 5-(2-methyl propyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that 5-(2-chloroethyl)furan-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that 5-methyl-2-furfural was used to replace 3-methoxy-4-benzyloxybenzaldehyde and 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that tryptamine was used to replace 3-methoxy-4-benzyloxyphenylethylamine and 5-(2-methylpropyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that tryptamine was used to replace 3-methoxy-4-benzyloxyphenylethylamine and 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that 6-methoxytryptamine was used to replace 3-methoxy-4-benzyloxyphenylethylamine and 5-(2-methylpropyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 78, except that 6-methoxytryptamine was used to replace 3-methoxy-4-benzyloxy phenylethylamine and 5-(2-chloroethyl)thiophene-2-acetic acid was used to replace thiophene-2-acetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(2'-hydroxyethoxymethyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(dimethylaminomethyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(morpholine-N-methyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-((N-methyl)piperazine-N-methyl)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 31, except that benzooxazole-5-acetic acid was used to replace 2,5-dimethoxyphenylacetic acid.
  • the titled product was prepared by the same procedure as that in example 80, except that 2-methylpropionyl chloride was used to replace acetyl chloride and benzofuran-5-acetic acid was used to replace 3-methoxy-4-benzyloxyphenylethylamine.
  • the titled product was prepared by the same procedure as that in example 3, except that 7-(morpholine-N-ethoxy)-8-methoxy-3-isochromanone was used to replace 7-benzyloxy-8-methoxy-3-isochromanone.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(acetyldimethylamino)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(carboxyethyl)thiophene-2-acetic acid was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that ethyl 5-(ethylol)thiophene-2-acetate was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the titled product was prepared by the same procedure as that in example 80, except that 5-(methoxycarbonylethyl)thiophene-2-acetic acid was used to replace ethyl 5-ethylthiophene-2-acetate.
  • the compound of the invention at different concentrations (10 -5 M-10 -11 M), an isotope receptor ligand and a receptor protein were loaded into a reaction tube, incubated at 30 °C in a water bath for 60min, and then terminated in a refrigerator.
  • the mixture was filtered through suction filtration using GF/C glass fiber paper on a Millipore filter (millipore) cell sample collector, and dried.
  • the resulting sample was placed into a 0.5 mL tube, added with 500 ⁇ L of liquid scintillation fluid, and counted for measuring the intensity of radioativity.
  • (1) materials for receptor construction and cell culture Escherichia coli. DH5 ⁇ strain; insect virus transfer vector pVL1393 plasmid; BaculoGold linear Chinese baculovirus DNA, purchased from ParMingen company; mkD1RcDNA; rD2R cDNA; various restriction endonucleases, TaqDNA polymerase, T4 ligase, etc., LB medium; insect cell culture TNM-FH.
  • Escherichia coli. DH5 ⁇ strain insect virus transfer vector pVL1393 plasmid
  • BaculoGold linear Chinese baculovirus DNA purchased from ParMingen company
  • mkD1RcDNA rD2R cDNA
  • various restriction endonucleases TaqDNA polymerase, T4 ligase, etc.
  • LB medium insect cell culture TNM-FH.
  • the tested compounds have very strong affinity on dopamine D1 and D2 receptors. Further, some compounds of the present invention exhibit a strong affinity on 5-HT 1A .
  • diarylo[a,g]quinlizines of the invention have relatively low toxicity and good solubility.
  • the preparation method for the diarylo[a,g]quinlizines and derivatives of the invention has advantages of, for example, mild reaction condition, abundant and readily available raw materials, simple operation and post-treatment, good selectivity, etc.
  • the diarylo[a,g]quinlizines and derivatives thereof according to the invention have excellent selectivity among different subtypes of serotonin receptors and dopamine receptors.
  • the compounds of the invention can be used in preparing a medicament for treating a disease relating to nervous system, especially to the dopamine receptors D1 and D2 as well as serotonin receptors 5-HT 1A and 5-HT 2A .

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (4)

  1. Diarylo[a,g]chinolizin-Verbindung, Enantiomer, Diastereoisomer, Racemat, pharmazeutisch geeignetes Salz, kristallines Hydrat oder Solvat davon, wobei die Diarylo[a,g]chinolizin-Verbindung wie folgt ist:
    Figure imgb0196
    Figure imgb0197
    Figure imgb0198
    Figure imgb0199
    Figure imgb0200
    Figure imgb0201
    Figure imgb0202
    Figure imgb0203
    Figure imgb0204
    Figure imgb0205
    Figure imgb0206
    Figure imgb0207
    Figure imgb0208
    Figure imgb0209
    Figure imgb0210
    Figure imgb0211
    Figure imgb0212
    Figure imgb0213
    Figure imgb0214
    Figure imgb0215
    Figure imgb0216
    Figure imgb0217
    Figure imgb0218
    Figure imgb0219
    Figure imgb0220
    Figure imgb0221
    Figure imgb0222
    Figure imgb0223
    Figure imgb0224
    Figure imgb0225
    Figure imgb0226
  2. Verfahren zur Herstellung der Diarylo[a,g]chinolizin-Verbindung, des Enantiomers, Diastereoisomers, Racemats, pharmazeutisch verträglichen Salzes, kristallinen Hydrats oder Solvats davon nach Anspruch 1, wobei das Verfahren nach einer der folgenden Methoden durchgeführt wird:
    Methode A.
    Figure imgb0227
     wobei die Methode A umfasst:
    a) Umsetzen von a1 mit a2 durch eine Aminoester-Austauschreaktion in einem polaren protischen Lösungsmittel, um a3 zu erhalten;
    b) Umsetzen von a3 mit einem Acylierungsmittel durch eine Acylierungsreaktion in Gegenwart einer Base, um a4 zu erhalten;
    c) Dehydratisieren und Cyclisieren von a4 in Gegenwart eines Kondensationsmittels, um a5 zu erhalten;
    d) asymmetrisches Reduzieren von a5 in Gegenwart eines Hydrierungsreagenzes und eines chiralen Katalysators, um a6 zu erhalten;
    e) Hydrolysieren von a6 in Gegenwart einer Base, um a7 zu erhalten;
    f) Halogenieren von a7 mit einem Halogenierungsreagenz und anschließende direktes Cyclisieren in Gegenwart einer Base, um a8 zu erhalten;
    g) wahlweise, wenn a8 eine zu entfernende Schutzgruppe aufweist, wird a8 entschützt, um die Schutzgruppe zu entfernen;
    Methode B:
    Figure imgb0228
     wobei die Methode B umfasst:
    1) Umsetzen von a1 mit b2 durch eine Kondensationsreaktion in Gegenwart eines Kondensationsmittels, um b3 zu erhalten;
    2) Dehydratisierung und Cyclisierung von b3 in Gegenwart eines Kondensationsmittels, um b4 zu erhalten;
    3) asymmetrische Reduktion von b4 in Gegenwart eines chiralen Katalysators und eines Hydrierungsreagens, um b5 zu erhalten; und
    4) Umsetzen von b5 mit einem substituierten Aldehyd R4CHO durch eine Pictet-Spengler-Reaktion unter sauren Bedingungen, um b6 zu erhalten;
    wobei in den obigen Verfahren A und B die Ringe A und D sowie die Substituenten identisch definiert sind wie in Anspruch 1.
  3. Pharmazeutische Zusammensetzung, umfassend eine therapeutisch wirksame Menge eines oder mehrerer Bestandteile, ausgewählt aus der Gruppe bestehend aus Diarylo[a,g]chinolizin-Verbindung, Enantiomer, Diastereoisomer, Racemat, pharmazeutisch geeignetem Salz, kristallinem Hydrat oder Solvat davon nach Anspruch 1, und einen oder mehrere pharmazeutisch geeignete Träger.
  4. Diarylo[a,g]chinolizinverbindung, Enantiomer, Diastereoisomer, Racemat, pharmazeutisch geeignetes Salz, kristallines Hydrat oder Solvat davon nach Anspruch 1 zur Verwendung bei der Herstellung eines Medikaments zur Behandlung oder Vorbeugung einer Krankheit, die mit Dopaminrezeptoren und 5-HT-Rezeptoren zusammenhängt, ausgewählt aus Schizophrenie, Parkinson-Krankheit, Manie, Depression, Drogenabhängigkeit oder Migräne.
EP13787305.5A 2012-05-09 2013-05-09 Diaryl[a,g-]chinolizidinverbindung, herstellungsverfahren dafür, pharmazeutische zusammensetzung und verwendungen davon Active EP2848617B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210142903.4A CN103387583B (zh) 2012-05-09 2012-05-09 二芳基并[a,g]喹嗪类化合物、其制备方法、药物组合物及其应用
PCT/CN2013/000549 WO2013166862A1 (zh) 2012-05-09 2013-05-09 二芳基并[a,g]喹嗪类化合物、其制备方法、药物组合物及其应用

Publications (3)

Publication Number Publication Date
EP2848617A4 EP2848617A4 (de) 2015-03-18
EP2848617A1 EP2848617A1 (de) 2015-03-18
EP2848617B1 true EP2848617B1 (de) 2022-01-12

Family

ID=49532015

Family Applications (1)

Application Number Title Priority Date Filing Date
EP13787305.5A Active EP2848617B1 (de) 2012-05-09 2013-05-09 Diaryl[a,g-]chinolizidinverbindung, herstellungsverfahren dafür, pharmazeutische zusammensetzung und verwendungen davon

Country Status (6)

Country Link
US (1) US9751882B2 (de)
EP (1) EP2848617B1 (de)
JP (1) JP5940729B2 (de)
CN (1) CN103387583B (de)
ES (1) ES2909537T3 (de)
WO (1) WO2013166862A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SG10202004688SA (en) 2004-03-01 2020-06-29 Dolby Laboratories Licensing Corp Multichannel Audio Coding
CN107303298B (zh) * 2016-04-21 2021-06-22 中国科学院上海药物研究所 一种苯[g]杂芳基并[a,g]喹嗪类化合物的药物用途及其制备方法
WO2019034031A1 (zh) * 2017-08-14 2019-02-21 中国科学院上海药物研究所 一类四氢原小檗碱类化合物，其制备方法、用途及药物组合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022858A1 (en) * 1993-04-06 1994-10-13 Abbott Laboratories Tetracyclic compounds as dopamine agonists
WO1997036902A1 (en) * 1996-04-02 1997-10-09 Abbott Laboratories TRANS-2,6-, 3,6- AND 4,6-DIAZA-5,6,6a,7,8,12b-HEXAHYDROBENZO[C]PHENANTHRENE COMPOUNDS AS DOPAMINE AGONISTS
WO2007006212A1 (en) * 2005-07-08 2007-01-18 Shanghai Institute Of Materia Medica, Chinese Academy Of Siences Tetrahydroprotoberberine compounds, the synthetic method and the use thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3103513A (en) * 1963-09-10 Process for preparing hexadehy-
JPS5024299A (de) * 1973-06-28 1975-03-15
US4956365A (en) * 1987-04-13 1990-09-11 Syntex (U.S.A.) Inc. Decahydro-8H-isoquino(2,1-g)(1,6)naphthyridine derivatives and related compounds
US4791108A (en) * 1987-04-13 1988-12-13 Syntex (U.S.A.) Inc. Sulfonyl-decahydro-8H-isoquino[2,1-G][1,6]-naphthyridines and related compounds useful as α2 -blockers
KR930002346A (ko) 1991-07-17 1993-02-23 앨런 크루비너 데카히드로-8H-이소퀴노[2, 1-g][1, 6]나프티리딘 및 데카히드로벤조[a]피롤로[2, 3-e]퀴놀리진 유도체
US5229387A (en) * 1991-09-20 1993-07-20 Syntex (U.S.A.) Inc. Decahydro-8H-isoquino[2,1-g][1,6]naphthyridine and decahydrobenzo[a]pyrrolo [2,3-e]quinolizine derivatives
CN100345848C (zh) 2003-09-29 2007-10-31 中国科学院上海药物研究所 左旋卤代斯库利啉盐及其制备方法和用途
CN1900076B (zh) 2005-07-08 2011-06-22 中国科学院上海药物研究所 四氢原小檗碱类化合物及其制备方法和用途
CN100528872C (zh) * 2006-07-26 2009-08-19 中国科学院上海药物研究所 一类四氢原小檗碱类化合物、其制备方法及其组合物和用途
CN102256973B (zh) * 2008-12-23 2014-06-11 西威埃医药技术（上海）有限公司 用于降低脂类水平的化合物、组合物和方法
CN103664974B (zh) * 2012-09-17 2016-12-21 中国科学院上海药物研究所 芳基[a]吲哚[2,3-g]并喹嗪类化合物、其制备方法、药物组合物及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994022858A1 (en) * 1993-04-06 1994-10-13 Abbott Laboratories Tetracyclic compounds as dopamine agonists
WO1997036902A1 (en) * 1996-04-02 1997-10-09 Abbott Laboratories TRANS-2,6-, 3,6- AND 4,6-DIAZA-5,6,6a,7,8,12b-HEXAHYDROBENZO[C]PHENANTHRENE COMPOUNDS AS DOPAMINE AGONISTS
WO2007006212A1 (en) * 2005-07-08 2007-01-18 Shanghai Institute Of Materia Medica, Chinese Academy Of Siences Tetrahydroprotoberberine compounds, the synthetic method and the use thereof

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
A. I. MEYERS ET AL: "A novel entry into indole alkaloids", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 47, no. 11, 1 May 1982 (1982-05-01), pages 2229 - 2231, XP055371292, ISSN: 0022-3263, DOI: 10.1021/jo00132a063 *
A. YU POTAPOV ET AL: "SYNTHESIS OF THE NOVEL HETEROCYCLIC SYSTEM 8,13,13b,14-TETRAHYDROINDOLO- [2,3-a]PYRIMIDO[5,4-g]QUINOLIZIN-5(7H)-ONE", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, 11 January 2012 (2012-01-11), pages 1304 - 1305, XP055371296, Retrieved from the Internet <URL:http://rd.springer.com/content/pdf/10.1007/s10593-012-0908-3.pdf> [retrieved on 20170510] *
AUDIA J E ET AL: "Potent, selective tetrahydro-beta-carboline antagonists of the serotonin 2B contractile receptor in the rat stomach fundus", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 39, 1 January 1996 (1996-01-01), pages 2773 - 2780, XP002167539, ISSN: 0022-2623, DOI: 10.1021/JM960062T *
JAHANGIR MICHAEL A. BROOK ET AL: "8 H -Isoquino[2,1- b ][2,7]naphthyridin-8-ones: synthesis of the Alangium alkaloids, alangimaridine and alangimarine", CANADIAN JOURNAL OF CHEMISTRY, vol. 65, no. 10, 1 October 1987 (1987-10-01), CA, pages 2362 - 2368, XP055371242, ISSN: 0008-4042, DOI: 10.1139/v87-394 *
ROBERT C. ELDERFIELD ET AL: "Alstonia Alkaloids. IX. Synthesis of Alstonilinol and Analogs by Reductive Ring Closure 1", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 23, no. 7, 1 July 1958 (1958-07-01), pages 949 - 953, XP055371278, ISSN: 0022-3263, DOI: 10.1021/jo01101a003 *
S C PAKRASHI ET AL: "NOVEL BENZOPYRIDOUUINOLIZINE BASES FROM ALANGIUM LAMARCKII THW", TETRAHEDRON LETTERS, 1 January 1980 (1980-01-01), pages 2667 - 2670, XP055371208, Retrieved from the Internet <URL:http://www.sciencedirect.com/science/article/pii/S0040403900928351/pdf?md5=995dcebc4d3be215a3eace11e95128b7&pid=1-s2.0-S0040403900928351-main.pdf> [retrieved on 20170510] *

Also Published As

Publication number Publication date
WO2013166862A1 (zh) 2013-11-14
EP2848617A4 (de) 2015-03-18
CN103387583A (zh) 2013-11-13
JP2015515994A (ja) 2015-06-04
US9751882B2 (en) 2017-09-05
ES2909537T3 (es) 2022-05-06
JP5940729B2 (ja) 2016-06-29
EP2848617A1 (de) 2015-03-18
CN103387583B (zh) 2018-04-13
US20150141419A1 (en) 2015-05-21

Similar Documents

Publication Publication Date Title
CA2981661C (en) Heterocyclic compounds as lsd1 inhibitors
EP4328225A1 (de) Inhibitor eines heterocyclischen derivats und herstellungsverfahren dafür und anwendung davon
EP0296597B1 (de) Hexacyclische Verbindungen
US5658920A (en) Substituted 1H,12H-benz-[DE]pyrano[3&#39;,4&#39;:6,7] indolizino[1,2-B]quinoline-10,13(9H,15H)-dione compound
Yao et al. Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors
TW201206944A (en) Morpholine compounds
CN104995191A (zh) 三环喹啉和喹喔啉衍生物
JP2004501860A (ja) ノルエピネフリン、ドーパミンおよびセロトニンの再取り込みを遮断するための、４−フェニル置換テトラヒドロイソキノリン類およびその利用
CN102796096B (zh) 六氢二苯并[a,g]喹嗪类化合物、其制备方法、药物组合物及其应用
PT2252611E (pt) (di-hidro)pirrolo[2,1-a]isoquinolinas
AU2017208119B2 (en) 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine dopamine D3 ligands
EP2848617B1 (de) Diaryl[a,g-]chinolizidinverbindung, herstellungsverfahren dafür, pharmazeutische zusammensetzung und verwendungen davon
CA2440014C (en) Beta-carboline derivatives and its pharmaceutical use against depression and anxiety
CA2688395A1 (en) Therapeutic pyrazoloquinoline derivatives
JP7273454B2 (ja) 物質使用再発のための非筋ミオシンｉｉ阻害剤
JP6033085B2 (ja) 三環式誘導体ならびにそれらの医薬用途および組成物
Gabet et al. Identification of N-benzyltetrahydroisoquinolines as novel anti-neuroinflammatory agents
EP2116538B1 (de) Kondensiertes tetrahydrochinolin-derivat und seine verwendung für medizinische zwecke
US4511569A (en) Tricyclic lactams and derivatives useful in increasing cardiac contractility
CA3120614A1 (en) Inhibitors of gli1 as therapeutic agents
JP2008519820A (ja) Ｃｎｓ障害の治療のためのアザベンゾオキサゾール
Tverdokhlebov et al. Synthesis of pyrrolo [2, 3-c] 2, 7-naphthyridine derivatives by cascade heterocyclization reaction of 2-amino-4-cyanomethyl-6-dialkylamino-3, 5-pyridinedicarbonitriles
MXPA01013229A (es) Cromero?14,3,3-de]isoquinolinas utiles como ligandos potentes para el receptor de dopamina.
US10174052B2 (en) Quinuclidine compounds as α-7 nicotinic acetylcholine receptor ligands
US9012470B2 (en) Therapeutic 5,6,5-tricyclic analogs

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20141208

A4 Supplementary search report drawn up and despatched

Effective date: 20150122

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20151210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

INTG Intention to grant announced

Effective date: 20210609

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTC Intention to grant announced (deleted)
INTG Intention to grant announced

Effective date: 20210729

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602013080679

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 1462314

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220215

REG Reference to a national code

Ref country code: NL

Ref legal event code: FP

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20220324

Year of fee payment: 10

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2909537

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20220506

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG9D

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 1462314

Country of ref document: AT

Kind code of ref document: T

Effective date: 20220112

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20220518

Year of fee payment: 10

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220512

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220412

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220412

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20220523

Year of fee payment: 10

Ref country code: IT

Payment date: 20220531

Year of fee payment: 10

Ref country code: FR

Payment date: 20220523

Year of fee payment: 10

Ref country code: ES

Payment date: 20220617

Year of fee payment: 10

Ref country code: DE

Payment date: 20220530

Year of fee payment: 10

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220413

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20220523

Year of fee payment: 10

Ref country code: BE

Payment date: 20220518

Year of fee payment: 10

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220512

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602013080679

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

26N No opposition filed

Effective date: 20221013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220509

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20220509

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230413

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602013080679

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20230601

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20230509

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20230531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230510

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230531

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20130509

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230509

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20231201

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20220112

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20230509